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A. Spencer et al.
The benefit of D-Vd was also maintained in patients regardless of cytogenetic risk, as D-Vd but not Vd induced MRD negativity in high-risk patients, suggesting that this combination may improve historically poor outcomes in this population.25-28
D-Vd–treated patients continued to receive daratumum- ab monotherapy after completing 8 cycles of Vd, reflected by the longer treatment duration (median: D-Vd, 13.4 months; Vd, 5.2 months). With longer follow up, the depth of response in the D-Vd arm, including CR rates and MRD negativity, continued to improve over time after patients entered the monotherapy phase, supporting the benefit of continued daratumumab treatment. Analyses are ongoing to quantify the therapeutic impact of mainte- nance therapy with single-agent daratumumab.
This was the first randomized, phase 3 clinical trial of RRMM with prospective MRD evaluation. MRD-negative status was associated with prolonged PFS in both treat- ment groups, but D-Vd increased MRD-negative rates at all sensitivity thresholds and evaluated subgroups. Additional longitudinal MRD evaluation in CASTOR is ongoing and the potential benefit of daratumumab- induced MRD negativity is being explored in studies of newly diagnosed MM (ALCYONE clinicaltrials.gov identifier 02195479; clinicaltrials.gov identifier 02252172; clinicaltrials.gov identifier 02541383; clinicaltrials.gov identifier 03301220. These studies aim to further validate MRD- negative status as a surrogate study endpoint.
Several new agents for RRMM have been approved based on robust clinical data, including carfilzomib29 and ixazomib30 (second-generation PIs), pomalidomide31,32 (a third-generation immunomodulatory drug), daratu- mumab13,14,33-35 and elotuzumab36 (monoclonal antibodies), and panobinostat4 (a histone deacetylase inhibitor). Approvals of many of these agents were based on superi- ority of PFS in phase 3 trials. These studies are beginning to report OS outcomes. In the ENDEAVOR study, carfil- zomib and dexamethasone conferred an additional OS benefit of 7.6 months versus Vd.37 OS analysis in CASTOR is ongoing.
Clinical trials are not usually powered to determine optimal treatment sequencing or the most effective regi- men for each disease subset.38 Although meta-analyses provide useful guides for selecting treatment options, physicians need to consider many different factors to opti- mize individual regimens, including numbers and types of prior regimens, duration of response to prior therapy, tox- icities with prior therapies, disease aggressiveness, and performance status or frailty.38,39 Based on the current find- ings, and the findings of other studies,40 daratumumab combined with other anti-myeloma drugs such as borte-
zomib or lenalidomide, may provide significant benefit in patients with early relapsed MM regardless of prior treat- ment exposure. It remains to be seen whether this trans- lates to prolonged survival.
The safety profile of D-Vd remained unchanged with approximately 1 year of additional follow up from the pri- mary analysis,13 with no new unexpected TEAEs observed. Preliminary data indicated that adding a third agent to Vd did not worsen HRQoL, an evaluation that was not presented in the primary analysis. More SPMs were reported with D-Vd versus Vd (4.1% versus 0.4%); this rate is similar to the incidence of SPMs reported for patients in POLLUX (5.7% for both D-Rd and Rd; manu- script in preparation) and for RRMM patients in general (between 1%-6%).41 At clinical cut-off, all patients in the Vd group had discontinued or completed 8 treatment cycles, whereas 41% of patients receiving D-Vd remained on daratumumab treatment. Therefore, more frequent monitoring during active treatment may explain why a greater number of TEAEs (including grade 3 or 4 events) and SPMs were reported with D-Vd. After 8 cycles of D-Vd, patients were monitored every 4 weeks during daratumumab dosing, whereas patients who received Vd who did not receive daratumumab monotherapy were followed for survival via phone calls every 16 weeks fol- lowing disease progression.
In conclusion, the original finding of significant benefit of D-Vd over Vd was confirmed regardless of treatment history or cytogenetic risk. Importantly, this clinical bene- fit was achieved without any emergent safety issues or decline in HRQoL. These results provide further support for the addition of daratumumab to a standard of care reg- imen in RRMM, particularly at first relapse. The CASTOR study is ongoing, and the feasibility of MRD negativity as a surrogate for OS in RRMM continues to be investigated. An analysis of OS will be conducted after 320 events are observed.
Funding
This study was sponsored by Janssen Research & Development, LLC. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
Acknowledgments
Medical writing and editorial support were provided by Jason Jung, PhD and Kristin Runkle, PhD of MedErgy, and were funded by Janssen Global Services, LLC.
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